Authors :
Presenting Author: Elisabeth Adetta Heynold, MD – Stanford University, School of Medicine
Thomas Hainmueller, MD, PhD – New York University, Grossman School of Medicine
Ivan Soltesz, PhD – Stanford University
György Buzsáki, MD PhD – New York University, Grossman School of Medicine
Rationale:
The dentate gyrus is the major gateway for information to the hippocampus. It aids in the selection and segregation of excitation patterns that arrive from other brain regions. A specialized cytoarchitecture controls this gating function and is constituted by powerful inhibitory interneurons. The two major classes of interneurons in the dentate gyrus are the dendrite-inhibiting somatostatin- and the soma-inhibiting parvalbumin-expressing interneurons. Excitation patterns arriving from the entorhinal cortex can be physiological, as in the case of dentate spikes, or pathological, as in interictal epileptiform discharges (IEDs) or seizures. Dentate spikes are associated with learning and memory consolidation and retrieval, whereas IEDs disrupt cognitive function. Methods:
(1) We investigated the differential role that distinct GABA-ergic interneuron subgroups play in the propagation of IEDs in mouse models of neurodegenerative diseases, a kainate model of temporal epilepsy, and as a model for interictal epileptiform discharges, an Alzheimer's mouse model (APP/PS1). The animals were chronically implanted with high-density silicon probes and optic fibers for optogenetic manipulation of different interneuron types. (2) We further developed a closed-loop system that interrupts IEDs within microseconds by optogenetic activation of dentate gyrus interneurons. (3) We are evaluation cognitive performance while the mice performed a radial 8 arm memory and spatial orientation task. (4) By performing multi-region electrophysiological recordings, we investigate the extent and patterns of propagation of IEDs and will correlate these spatiotemporal features with behavioral memory deficits.
Results: (1, 2) Results show that closed-loop optogenetic interneuron stimulation with microsecond precision that reliably distinguishes dentate spikes from IEDs is feasible, and can powerfully suppress hippocampal population activity. (3,4) Effects on cognitive performance and correlation to propagation patterns of IEDs are currently under evaluation.
Conclusions: Blocking aberrant sub-clinical excitation at the level of the dentate gyrus might be a treatment target to improve cognition in temporal lobe epilepsy. It is a promising tool to disrupt pathological network activation during IEDs and potentially improve memory function in mouse models.
Funding:
This work was supported by RO1MH122391, RO1MH139216 and U19NS107616 (GB), a NARSAD Young Investigator Grant (32940) from the Brain & Behavior Research Foundation (TH), DFG Walter Benjamin Fellowship HE 9600/2-1 (EAH) and Forschungsstipendium HA 8939/1-1 (TH), and Finding a Cure for Epilepsy and Seizures (FACES) 2024 Research Grant (EAH, TH).